Abstract
In up to 10%
of patients who present with ventricular tachycardia (VT), obvious
structural heart disease is not identified. In such patients, causes of
ventricular arrhythmia include right ventricular outflow tract (RVOT)
VT, extrasystoles, idiopathic left ventricular tachycardia (ILVT),
idiopathic propranolol-sensitive VT (IPVT), catecholaminergic
polymorphic VT (CPVT), Brugada syndrome, and long QT syndrome (LQTS).
RVOT VT, ILVT, and IPVT are referred to as idiopathic VT and generally
do not have a familial basis. RVOT VT and ILVT are monomorphic, whereas
IPVT may be monomorphic or polymorphic. The idiopathic VTs are
classified by the ventricle of origin, the response to pharmacologic
agents, catecholamine dependence, and the specific morphologic features
of the arrhythmia. CPVT, Brugada syndrome, and LQTS are inherited ion
channelopathies. CPVT may present as bidirectional VT, polymorphic VT,
or catecholaminergic ventricular fibrillation. Syncope and sudden death
in Brugada syndrome are usually due to polymorphic VT. The
characteristic arrhythmia of LQTS is torsades de pointes. Overall,
patients with idiopathic VT have a better prognosis than do patients
with ventricular arrhythmias and structural heart disease. Initial
treatment approach is pharmacologic and radiofrequency ablation is
curative in most patients. However, radiofrequency ablation is not
useful in the management of inherited ion channelopathies. Prognosis
for patients with VT secondary to ion channelopathies is variable.
High-risk patients (recurrent syncope and sudden cardiac death
survivors) with inherited ion channelopathies benefit from implantable
cardioverter-defibrillator placement. This paper reviews the mechanism,
clinical presentation, and management of VT in the absence of
structural heart disease.

It is
estimated that 10% of patients who present with ventricular tachycardia
(VT) have no obvious structural heart disease.1
An absence of structural heart disease is usually suggested if an
electrocardiogram (ECG) (except in Brugada syndrome and long QT
syndrome [LQTS]), echocardiogram, and coronary arteriogram collectively
are normal.2 However,
structural abnormalities may be identified by magnetic resonance
imaging (MRI) even if all other test results are normal.3 In addition, focal dysautonomia in the
form of localized sympathetic denervation has been reported in patients
with VT and no other obvious structural heart disease.4
Types of VT that occur in the
absence of structural heart disease include right ventricular (RV)
monomorphic extrasystoles, RV outflow tract (RVOT) VT, left ventricular
(LV) outflow tract (LVOT) VT, idiopathic LV tachycardia (ILVT),
idiopathic propranolol-sensitive (automatic) VT (IPVT),
catecholaminergic polymorphic VT (CPVT), Brugada syndrome, and LQTS. RV
monomorphic extrasystoles, RVOT VT, LVOT VT, ILVT, and IPVT are
referred to as idiopathic VT. Idiopathic VT from the RVOT and LV are
monomorphic and generally not familial. Idiopathic VTs are classified
with respect to the ventricle of origin, the response to pharmacologic
agents, evidence of catecholamine dependence, and the specific
morphologic features (QRS morphology, axis, pattern, and whether
tachycardia is repetitive, nonsustained, or sustained) (Table 1). CPVT, Brugada syndrome,
and LQTS are inherited ion channelopathies.

In this review of VT in the
absence of structural heart disease, we discuss the clinical
recognition and management of idiopathic VT and inherited ion
channelopathies. The articles were selected for review from a search of
PubMed using search terms “idiopathic VT,” “LQTS,” “Brugada syndrome,”
and “CPVT.” For each topic, articles focusing on diagnosis and
management were preferentially selected.

RV Monomorphic Extrasystoles and
RVOT VT

RV
monomorphic extrasystoles and RVOT VT appear to be on a continuum of
the same process. RV monomorphic extrasystoles are characterized by
ventricular ectopy with left bundle branch block (LBBB) morphology,
and, on ECG, the QRS axis is directed inferiorly. Ventricular ectopy of
this type was defined in 1969 and considered “typical for normal
subjects.”5 Resting ECG in
these patients has no identifiable abnormalities, and the prognosis is
generally benign. These extrasystoles occur more often during the day
than at night and are transiently suppressed by sinus tachycardia.6 The extrasystoles may diminish or
disappear with exercise during stress testing. The site of origin is
most often the RVOT and, to a lesser extent, the interventricular
septum in the region of the RVOT.7
An echocardiogram is normal in most of these patients,8 although
anatomic changes, such as focal thinning and fatty replacement of the
RVOT, have been demonstrated with MRI.3
A potential
relationship between these seemingly benign ventricular extrasystoles
of RVOT origin and structural cardiac disease (arrhythmogenic RV
dysplasia [ARVD]) has been investigated.9
Sixty-one patients with RVOT ventricular extrasystoles were contacted
15 years after their initial visit; no patient had died of sudden death
nor developed ARVD in this study. Two-thirds of the patients were
asymptomatic, and, in half, the ventricular ectopy had disappeared.
Focal fatty replacement of the RV was present on MRI in most patients,
in contrast to the diffuse pattern of fatty replacement observed in
patients with ARVD.
In North
America, 70% of cases of idiopathic VT arise from the RV, chiefly the
RVOT just inferior to the pulmonic valve.2
The characteristic morphology of RVOT VT is a wide QRS complex
tachycardia with LBBB pattern and an inferior axis.10 Among the outflow
tract tachycardias, 90% originate from the RVOT and 10% from the LVOT.
Either or both forms may be found in the same patient. RVOT VT is
usually diagnosed in the third to fifth decade of life, although cases
at the extremes of age have been reported. Most patients (80%) present
with palpitations or presyncope (50%) but rarely present with frank
syncope. Exercise or emotional stress usually precipitates the
tachycardia. Sudden death is rare.
Two phenotypic
forms of RVOT VT occur: nonsustained, repetitive, monomorphic VT (Fig. 1)11
and paroxysmal, exercise-induced, sustained VT (Fig. 2). Both are terminated by the
administration of adenosine. Specific ECG characteristics have been
described to differentiate RVOT VT from LVOT VT.12 LVOT VT may originate from either the
supravalvular region of a coronary cusp or the infravalvular
endocardial region of a coronary cusp of the aortic valve. The
distinction between supravalvular and infravalvular location of the
tachycardia has important therapeutic implications, particularly if
radiofrequency (RF) ablation is performed. LVOT VT is suggested if the
ECG during VT shows an S wave in lead I and an R-wave transition in
lead V1 or V2. The absence of an S wave in V5 or V6 suggests a
supravalvular location, whereas an S wave in leads V5 and V6 indicates
an infravalvular location (Fig. 3).
In addition, in leads V1 and V2, an R:S amplitude ratio of 30% or more
or an R:QRS duration ratio of 50% or more suggests an LV (aortic sinus
cusp) origin of the tachycardia.13

Fig. 3. Electrocardiogram
illustrating left ventricular outflow tract ventricular tachycardia
(LVOT VT). The S wave in LI and R-wave transition in V1 suggest LVOT
VT. In addition, an R:S amplitude ratio of 30% and an R:QRS duration
ratio of 50% are seen. Presence of an S wave in leads V5 and V6
suggests an infravalvular origin of the tachycardia.

Exercise
stress testing is used frequently to initiate and evaluate RVOT VT
(unlike RV monomorphic extrasystoles, which are suppressed by sinus
tachycardia) but is not clinically helpful in most cases. Initiation of
the tachycardia depends on a critical heart rate that differs in each
patient. The VT may be initiated during exercise or recovery.14 ECG and echocardiogram in sinus rhythm
are usually normal, as is coronary angiography. MRI may show
abnormalities of the RV in up to 70% of patients, including focal
thinning, diminished systolic wall thickening, and abnormal wall motion.15
RVOT VT should
be distinguished from ARVD, a disorder with a more serious clinical
outcome. The VT in ARVD may have morphologic features similar to RVOT
VT (LBBB with inferior axis) but does not terminate with adenosine. In
ARVD, the resting 12-lead ECG typically shows inverted T waves in right
precordial leads. When present, RV conduction delay with an epsilon
wave (Fig. 4), best seen in
leads V1-V2, is helpful in the diagnosis of ARVD. Measurement of serum
brain natriuretic peptide may help distinguish ARVD from RVOT VT.16 The level of brain natriuretic peptide
is increased in ARVD, most likely due to increased expression by the
surviving myocytes surrounded by atrophic tissue, which is indicative
of the severity of RV dysfunction. Mechanisms of ARVD-related VT
include both reentry facilitated by slow conduction through areas of
fatty infiltration and increased automaticity.17
In ARVD, the areas typically affected on echocardiography or MRI
include the apex, interventricular septum below the tricuspid septal
leaflet, and the RVOT. In some cases, fatty infiltration of the LV
occurs. An RV biopsy and histopathologic characterization may help
determine the correct diagnosis.

Fig. 4. Electrocardiogram showing an
epsilon wave (arrow) in a patient with arrhythmogenic right ventricular
dysplasia.

The
differential diagnosis of RVOT VT also includes tachycardias associated
with atriofascicular fibers (Mahaim fibers), atrioventricular reentrant
tachycardia using a right-sided accessory pathway, and VT occurring in
patients after repair of tetralogy of Fallot.

Mechanism of
RVOT VT
Intracellular
calcium overload appears to be the principal underlying mechanism of
RVOT VT. Cytosolic calcium overload enhances the function of the Na+/Ca2+
exchanger, which leads to increasing inward current and delayed
afterdepolarization. When the inward current is of sufficient
threshold, the delayed afterdepolarization may cause another action
potential and initiate tachycardia. Cyclic adenosine monophosphate
(cAMP) has a substantial role in regulating intracellular calcium. When
the concentration of cAMP is increased, intracellular calcium levels
are high. Adenosine is effective in terminating RVOT VT because of its
ability to lower cAMP concentration.18
Beta-blockers are often effective because of their inhibition of
adenylate cyclase, which leads to a decrease of cAMP. Verapamil
inhibits L-type calcium channels, which decreases the concentration of
intracellular calcium and thereby has salutary effects.
Triggered
activity, rather than reentry or enhanced automaticity, as the cause of
RVOT VT is evidenced by termination with administration of adenosine
and inability to entrain. The tachycardia may be inducible by
programmed extrastimuli or by burst pacing the ventricle or atrium or
by infusion of isoproterenol. Somatic mutation involving the G-protein
signaling cascade could give rise to RVOT VT by disrupting adenosine
signaling. Of interest, mutation of the G protein subunit Alphai2
has been identified on myocardial biopsy in only the RVOT (the site of
origin) and not in myocardium remote from the site of VT.19

Treatment of
RVOT VT
Acute
termination of RVOT VT can be achieved by vagal maneuver or intravenous
administration of adenosine, 6 mg, which can be titrated up to 24 mg as
needed. Intravenous verapamil, 10 mg, given over 1 minute is an
alternative, provided the patient has adequate blood pressure and has a
previously established diagnosis of verapamil-sensitive VT. Lidocaine
also may be effective in some cases. Hemodynamic instability warrants
emergent cardioversion.
Long-term
treatment options for RVOT VT include medical therapy or RF ablation.
Medications, including beta-blockers or verapamil
(diltiazem is equally effective), have a 25% to 50% rate of efficacy.20 Alternative therapy includes class IA,
class IC, and class III agents including amiodarone.20 RF ablation now has cure rates of 90%,10 which makes it a preferable option,
given the young age of patients with RVOT VT. Ablation of sites at the
aortic sinus cusp has been successful for treatment of LVOT VT,13 but serious complications may occur,
including left main coronary artery occlusion. Coronary arteriography
before and during ablation is recommended to keep the tip of the
ablation catheter 1 cm away from the ostia of the coronary arteries.
After ablation, arteriography should be repeated to assess the patency
of coronary arteries. Epicardial foci of the LVOT remain a challenging
ablation target.

ILVT

Most VTs of LV origin are verapamil-sensitive intrafascicular
tachycardias. Intrafascicular tachycardia has a right bundle branch
block (RBBB) left-axis configuration in 90% to 95% of cases (exit site,
left posterior fascicle) and the rest have RBBB with a right-axis
pattern (exit site, left anterior fascicle). This form of VT is seen in
the second to fourth decade of life and occurs more often in men
(60%-80%).21 Symptoms
during tachycardia include palpitations, dizziness, presyncope, and
syncope. Sudden death is usually not seen, but one possible case has
been reported.22
A proposed
diagnostic triad of ILVT includes: 1) induction with atrial pacing, 2)
RBBB with left axis configuration, and 3) no evidence of structural
heart disease.23 A fourth
feature, verapamil sensitivity, has since been described.24

Mechanism of
ILVT
Focal reentry
appears to be the principal mechanism of ILVT. The tachycardia cycle
length can be increased with the administration of verapamil.25 Some evidence implicates the Purkinje
fibers of the fascicle as the area of slow conduction because of the
presence of high-frequency potentials (Purkinje potentials).26 Others have found late diastolic
potentials near the main trunk of the left bundle branch. Another
hypothesis implicates a false tendon extending from the inferoposterior
aspect of the LV to the basal septum as directly or indirectly having a
role in causing this arrhythmia.27

Treatment of
ILVT
In the acute
setting, this tachycardia responds to intravenous verapamil.
Termination with adenosine is rare, except for cases in which
isoproterenol is used for induction of the tachycardia. Long-term
therapy with verapamil is useful in mild cases and RF ablation is
highly effective (85%-90%) in those with severe symptoms.21 Identifying the focus of ablation may
involve recognition of Purkinje potential, late diastolic potential, or
earliest ventricular activation. Electroanatomic mapping may help
localize the area of slow conduction.28In
about 10% of cases of both ILVT and RVOT VT, a tachycardia with a
different morphology may be inducible after successful ablation of
clinical VT. This second tachycardia may be a cause for recurrence and
should preferably be ablated during the initial attempt.29

IPVT

This form of idiopathic VT usually occurs by the fifth decade of life
and can arise from the LV or RV.21
The morphology of the tachycardia may be monomorphic or polymorphic.
IPVT is not inducible with programmed stimulation. Isoproterenol
infusion usually induces this VT. Beta-blockers are effective in
terminating the tachycardia.

Treatment of
IPVTBeta-blockers are used to treat
this form of VT because they are effective in acute situations. There
is insufficient information available regarding long-term management of
IPVT. Survivors of sudden cardiac death may receive an implantable
cardioverter-defibrillator (ICD).

Inherited Channelopathies

CPVT

CPVT is characterized by a uniform pattern of
bidirectional polymorphic VT that can be easily and reproducibly
induced during exercise or catecholamine infusion. A third of patients
with CPVT have a family history of premature sudden death or
stress-related syncope.30
Exercise or acute emotion usually triggers syncope. Symptoms typically
manifest in childhood; onset in adulthood has been reported but is
uncommon.
The ryanodine
receptor 2 (RyR2) is important for the regulation of intracellular
calcium fluxes.31 In
patients with CPVT, the RyR2 gene is mutated, with
autosomal dominant inheritance suggested.32 One family with recessive
CPVT has been reported, and the gene responsible produces the protein
calsequestrin, which is functionally related to RyR2.33
CPVT and IPVT
can be distinguished by means of family history, morphology (CPVT is
usually bidirectional), age of onset (childhood vs the fifth decade),
and in some cases genetic testing (genetic defect vs idiopathic).

TreatmentBeta-blockers are the preferred
therapy for CPVT.30Beta-blockers may prevent syncope
and sudden death because adrenergic activation is the main mechanism of
delayed after depolarization-dependent triggered activity in these
patients.34 An ICD is
required in 30% of patients because of symptomatic recurrence of
life-threatening arrhythmia in spite of beta-blocker therapy.35

Brugada
SyndromeBrugada
syndrome is characterized by apparent RBBB with ST elevation in V1 to
V3 (V2 always present) (Fig. 5),
life-threatening cardiac arrhythmia (polymorphic VT) with no
demonstrable structural cardiac disease, and familial occurrence.36,37 The ECG changes
may mimic acute myocardial infarction. The ECG findings may not be
evident on resting 12-lead ECG but may be unmasked by flecainide or
procainamide.38,39
Two different types of ST elevation have been described: coved and
saddleback. The coved type is more relevant to the syndrome than is the
saddleback type.40 Genetic
analysis indicates that Brugada syndrome is due to mutation of the
SCN5A protein.41 The
incidence of the disease is about 5 per 10,000 persons. The
Brugada-type ECG (“Brugada sign”) may be much more common than is the
clinical syndrome.42 Sudden
death is usually due to polymorphic VT or ventricular fibrillation. The
disease predominantly affects young males.

Fig. 5. Electrocardiogram of a
patient with Brugada syndrome. The right bundle branch block pattern
with coved ST segment elevation (J-point elevation) is more than 2 mm,
particularly in lead V2.

The risk of sudden cardiac death
with Brugada syndrome is substantial. In a study of 334 patients with
typical Brugada-type ECG findings, which included symptomatic (cardiac
arrest and syncope) and asymptomatic patients, the risk of recurrent
events during 4 years of follow-up was 62% for those with cardiac
arrest and 19% for those with syncope.37
The asymptomatic group had an 8% event rate during 2 years of follow-up.

Management
ICD placement
is the treatment of choice in symptomatic patients. Asymptomatic
patients with Brugada-type ECG results should undergo
electrophysiologic testing . If ventricular arrhythmia is inducible
(two-thirds of patients are noninducible) the patient should receive an
ICD. Asymptomatic patients with normal baseline ECG do not require
further testing.

LQTS

LQTS is an uncommon disorder in the general population. It is an
inherited disorder, and mutations in 7 genes for LQTS have been
identified to date (Table 2).43 This syndrome was initially identified
in a family in which several children had syncope and sudden death. A
recessive inheritance pattern was identified, and the syndrome was
associated with deafness (Jervell and Lange-Nielsen syndrome). A
similar and more common disorder without deafness, inherited in an
autosomal dominant pattern, was subsequently identified (Romano-Ward
syndrome).

Clinical
Diagnosis
Syncope,
sudden cardiac death, or family screening of an affected individual is
the reason that physicians evaluate patients for LQTS. Prolonged QT
interval on ECG makes a diagnosis of LQTS likely. Medications that
prolong QT interval must be carefully excluded from the patient’s
medication list. Family history may be helpful for diagnosis of LQTS.
An incidental finding of prolonged QTc (not due to medications) in an
asymptomatic person is rare. Syncope and sudden death with LQTS occur
with higher frequency during adolescence.

Triggers of
Clinical Events
In patients
with LQT1 subtype, exercise seems to precipitate clinical events.44 In those with LQT2, acute arousal,
such as a sudden loud noise, tends to be a precipitating factor. In
patients with LQT3, clinical events occur at rest or during sleep.

Clinical Course
The risk of
cardiac events is higher with certain genotypes; patients with LQT1 and
LQT2 have higher risk of events than do those with LQT3.45 The risk of events also is higher
during adulthood in females and during adolescence (before puberty) in
males. The length of the QTc interval and the number of mutations also
increase the risk. Once a clinical event occurs (syncope or survival
after sudden cardiac death), recurrence is frequent.

ECG Findings
Eighty percent
of LQT1 and LQT2 carriers and 65% of LQT3 carriers have typical ECGs.
In LQT1, the T wave is broad-based with an indistinct onset. In LQT2,
bifid T waves may be seen in all 12 leads, and the ECG in LQT3 may have
a long isoelectric ST segment.46

Treatment
Adrenergic
modulation with beta-blockers is the most useful therapy in both
symptomatic and asymptomatic patients, even though beta-blockers do not alter QTc
interval.47 However, the
benefits of beta-blockers have not been proven
in a randomized trial. Surgical sympathectomy is an adjuvant treatment
and has been done rarely since the introduction of beta-blockers. Oral potassium may
be useful in certain genotypes.48
ICD placement, along with beta-blocker therapy, offers the
best protection in high-risk patients (survivors of sudden death and
those with recurrent syncope).49

Acquired LQTS and Torsades de
Pointes

Acquired prolongation of QT interval and pause-dependent, early
afterdepolarization-mediated torsades de pointes most often is caused
by medication and occasionally is caused by metabolic derangement
(hypokalemia and hypomagnesemia).50
Correction of electrolyte abnormalities and discontinuation of
precipitating drugs usually lead to amelioration of the arrhythmia.
Intravenous magnesium, although it may not have an effect on QT
interval, is highly effective at suppressing torsades de pointes.
Occasionally, a temporary transvenous pacemaker or isoprenaline may be
needed for effective management.

Diagnostic Approach to Ventricular
Arrhythmia in the Absence of Structural Heart Disease

The approach
to diagnosis of the subtypes of VT in the absence of heart disease
depends on the morphology of the tachycardia precipitating the clinical
event. If the presentation is monomorphic VT, RVOT VT, LVOT VT, ILVT,
and, rarely, IPVT are in the differential diagnosis. Specific ECG
criteria should help clarify the diagnosis (Fig. 6). If the inciting clinical
event is precipitated by polymorphic VT, torsades de pointes, or
ventricular fibrillation, the diagnosis may be approached by evaluating
the baseline or postresuscitation QTc interval (without antiarrhythmic
medications) (Fig. 7). If the
QTc is prolonged, LQTS and its subtypes are the predominant diagnoses,
provided drug-induced QTc prolongation can be reasonably excluded. If
the QTc is normal, Brugada syndrome, CPVT, and IPVT are the conditions
in the differential diagnosis. The Brugada ECG, either at baseline or
on induction with antiarrhythmic medication, may help identify Brugada
syndrome. Bidirectional VT and presentation during childhood identify
most patients with CPVT. IPVT remains a diagnosis when all other causes
are unlikely and the arrhythmia is propranolol sensitive. Genetic
testing may be helpful in the long-term evaluation of polymorphic VT
but acutely is not helpful.

Ventricular
arrhythmia in the absence of structural heart disease is a small subset
in the clinical spectrum of patients with VT. Overall, the prognosis is
better in patients with idiopathic ventricular arrhythmia than in
patients with structural heart disease and VT. Prognosis in hereditary
channelopathies is variable; CPVT, in particular, has a malignant
course when untreated. Understanding the different characteristics of
these tachycardias, their diagnostic features, and physiologic
substrates is essential for successful therapy and management. Stress
testing and response to antiarrhythmics each have an important role in
identifying the specific arrhythmia. RF ablation and placement of an
ICD are important in the overall management of specific arrhythmia.